CELL BIOLOGY AND TOXICOLOGY
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2022
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IF 6.819
Zhan Yujuan,Chen Qiugu,Song Yue,Wei Xianli,Zhao Tingxiu,Chen Bonan,Li Chengxi,Zhang Wenbo,Jiang Yanjun,Tan Yuhui,Du Biaoyan,Xiao Jianyong,Wang Kun
Autophagy is typically activated in cancer cells as a rescue strategy in response to cellular stress (e.g., chemotherapy). Herein, we found that Berbamine Hydrochloride (Ber) can act as an effective inhibitor of the late stage of autophagic flux, thereby potentiating the killing effect of chemotherapy agents. Lung carcinoma cells exposed to Ber exhibited increased autophagosomes, marked by LC3-II upregulation. The increased level of p62 after Ber treatment indicated that the autophagic flux was blocked at the late stage. The lysosome staining assay and cathepsin maturation detection indicated impaired lysosomal acidification. We found that Nox2 exhibited intensified co-localization with lysosomes in Ber-treated cells. Nox2 is a key enzyme for superoxide anion production capable of transferring electrons into the lysosomal lumen, thereby neutralizing the inner protons; this might explain the aberrant acidification. This hypothesis is further supported by the observed reversal of lysosomal cathepsin maturation by Nox2 inhibitors. Finally, Ber combined with cisplatin exhibited a synergistic killing effect on lung carcinoma cells. Further data suggested that lung carcinoma cells co-treated with Ber and cisplatin accumulated excessive reactive oxygen species (ROS), which typically activated MAPK-mediated mitochondria-dependent apoptosis. The enhanced anti-cancer effect of Ber combined with cisplatin was also confirmed in an in vivo xenograft mouse model. These findings indicate that Ber might be a promising adjuvant for enhancing the cancer cell killing effect of chemotherapy via the inhibition of autophagy. In this process, Nox2 might be a significant mediator of Ber-induced aberrant lysosomal acidification. Graphical abstract
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Food and Bioprocess Technology
·
2022
·Vol. 15
·期 8
·1821-1835
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IF 5.581
Bai Tingting,Li Jiaxing,Murtaza Ayesha,Iqbal Aamir,Zhu Lijuan,Zhang Jiao,Zhang Bing,Xu Xiaoyu,Pan Siyi,Hu Wanfeng
The effects of eugenol emulsion (EUG) on the browning of fresh-cut yam during storage and its inhibition mechanism were studied. The EUG treatment group had a significant anti-browning ability, and the 1.5% EUG treatment group had the best effect. During the whole storage period, the activities of peroxidase (POD) and phenylalanine ammonia-lyase (PAL) decreased significantly after 1.5% EUG treatment, especially on day 4, when the activity of POD and PAL was 3.2% and 23% of that of the control group, respectively. Molecular docking experiments showed that EUG inhibited PAL activity by binding to the active center of PAL, a key browning enzyme. A decrease in total phenol content was also observed. In addition, after EUG treatment, catalase (CAT) activity was significantly increased, preventing the accumulation of reactive oxygen species (ROS)-H 2 O 2 . EUG inhibited membrane lipid metabolism, 1.5% EUG delayed the emergence of lipoxygenase activity peak, and malondialdehyde (MDA) content decreased by 75.67% compared with the control on 4 d. In comparison with control, EUG increased the scavenging capacity of DPPH, ABTS, and iron-reducing antioxidant capacity (FRAP). The mechanism may be that EUG enhances antioxidant capacity, thereby reducing ROS-induced membrane lipid metabolism, therefore, lowering the synthesis and oxidation of phenolic compounds, and ultimately inhibiting browning.
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Antioxidants
·
2022
·Vol. 11
·期 8
·1498
·
IF 7.675
Chongshan Dai,Qinzhi Zhang,Linjie Shen,Gaurav Sharma,Haiyang Jiang,Zhanhui Wang,Jianzhong Shen
Quinocetone (QCT), a member of the quinoxaline 1,4-di-N-oxides (QdNOs) family, can cause genotoxicity and hepatotoxicity, however, the precise molecular mechanisms of QCT are unclear. This present study investigated the protective effect of quercetin on QCT-induced cytotoxicity and the underlying molecular mechanisms in human L02 and HepG2 cells. The results showed that quercetin treatment (at 7.5–30 μM) significantly improved QCT-induced cytotoxicity and oxidative damage in human L02 and HepG2 cells. Meanwhile, quercetin treatment at 30 μM significantly inhibited QCT-induced loss of mitochondrial membrane potential, an increase in the expression of the CytC protein and the Bax/Bcl-2 ratio, and an increase in caspases-9 and -3 activity, and finally improved cell apoptosis. Quercetin pretreatment promoted the expression of the phosphorylation of p38, Nrf2, and HO-1 proteins. Pharmacological inhibition of p38 significantly inhibited quercetin-mediated activation of the Nrf2/HO-1 pathway. Consistently, pharmacological inhibitions of the Nrf2 or p38 pathways both promoted QCT-induced cytotoxicity and partly abolished the protective effects of quercetin. In conclusion, for the first time, our results reveal that quercetin could improve QCT-induced cytotoxicity and apoptosis by activating the p38/Nrf2/HO-1 pathway and inhibiting the ROS/mitochondrial apoptotic pathway. Our study highlights that quercetin may be a promising candidate for preventing QdNOs-induced cytotoxicity in humans or animals.Keywords:quercetin;quinocetone;oxidative stress;apoptosis;p38/Nrf2/HO-1 pathway;NF-κB pathway
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INTERNATIONAL JOURNAL OF FOOD MICROBIOLOGY
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2022
·
IF 5.911
Weibin Ma,Luling Zhao,Eric T. Johnson,Yanli Xie,Mingming Zhang
Natural food flavour ( E )-2-hexenal, a green leaf volatile, exhibits potent antifungal activity on Aspergillus flavus , but its antifungal mechanism has not been fully elucidated. In this study, we evaluated ( E )-2-hexenal-induced apoptosis in A. flavus conidia and explored the underlying mechanisms of action. Evidence of apoptosis in A. flavus conidia were investigated by methods including fluorescent staining, flow cytometry, confocal laser scanning microscope, and spectral analysis. Results indicated that 4.0 μL/mL (minimum fungicidal concentration, MFC) of ( E )-2-hexenal application induced early markers of apoptotic cell death in A. flavus conidia with a rate of 38.4% after 6 h exposure. Meanwhile, typical hallmarks of apoptosis, such as decreased mitochondrial membrane potential (MMP), activated metacaspase activity, fragmented DNA, mitochondrial permeability transition pore (MPTP) opening and cytochrome c (Cyt C) release from mitochondria to the cytosol were also confirmed. Furthermore, intracellular ATP levels were reduced by 63.3 ± 3.6% and reactive oxygen species (ROS) positive cells increased by 31.1 ± 3.1% during A. flavus apoptosis induced by ( E )-2-hexenal. l -Cysteine (Cys), an antioxidant, could strongly block the excess ROS generation caused by ( E )-2-hexenal, which correspondingly resulted in a significant inhibition of MPTP opening and decrease of apoptosis in A. flavus , indicating that ROS palys a pivotal role in ( E )-2-hexenal-induced apoptosis. These results suggest that ( E )-2-hexenal exerts its antifungal effect on A. flavus conidia via a ROS-dependent mitochondrial apoptotic pathway.
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ACS Biomaterials Science & Engineering
·
2022
·
IF 5.395
Wei Ma,Huanli Zhang,Shuying Li,Zhiqiang Wang,Xiaodan Wu,Rui Yan,Fang Geng,Weijie Mu,Yingxue Jin
Chemodynamic therapy (CDT) based intracellular chemical reactions to produce highly cytotoxic reactive oxygen species has received wide attention. However, low efficiency of single CDT in weakly acidic pH and glutathione (GSH) overexpressed tumor cells has limited its clinical application. For this study were prepared two-dimensional metal–organic framework (MOF) to improve CDT efficiency based on the combined action of bimetallic CDT, consumption of overexpressed glutathione (GSH) in cells, folic acid (FA) induced tumor targeting and triphenylphosphine (TPP) induced mitochondrial targeting. With the use of Cu(II) as the central ion and tetrakis(4-carboxyphenyl)porphyrin (TCPP) as the ligand, two-dimensional Cu-MOF nanosheets were prepared, which were surface modified by manganese dioxide based on the in situ redox reaction between poly(allylamine hydrochloride) (PAH) and KMnO4 to obtain Cu-MOF@MnO2. Then FA and TPP were coupled with the nanosheets to form the title nanoplatform. Comprehensive physiochemical research has suggested that Cu(II) and MnO2 constituents in the nanoplatform could consume intracellular GSH and hydrogen peroxide to generate hydroxyl radicals through a Fenton-like reaction; meanwhile Cu(II) could undergo a Russell reaction to produce cytotoxic singlet oxygen. Detailed in vitro and in vivo biological experiments have revealed a good biosafety profile and a high tumor suppression effect. Therefore, the present research has realized multiple and efficient CDT effects with the aid of the sequential targeting of FA/TPP, also providing a strategy for the development of CDT drugs based on polymetallic organic frameworks.
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JOURNAL OF NANOBIOTECHNOLOGY
·
2021
·Vol. 19
·期 1
·1-20
·
IF 10.435
Xu Shibo,Chang Linna,Hu Yanan,Zhao Xingjun,Huang Shuocheng,Chen Zhenhua,Ren Xiuli,Mei Xifan
Background Healing of MRSA (methicillin-resistant Staphylococcus aureus) infected deep burn wounds (MIDBW) in diabetic patients remains an obstacle but is a cutting-edge research problem in clinical science. Surgical debridement and continuous antibiotic use remain the primary clinical treatment for MIDBW. However, suboptimal pharmacokinetics and high doses of antibiotics often cause serious side effects such as fatal complications of drug-resistant bacterial infections. MRSA, which causes wound infection, is currently a bacterium of concern in diabetic wound healing. In more severe cases, it can even lead to amputation of the patient's limb. The development of bioactive nanomaterials that can promote infected wound healing is significant.Results The present work proposed a strategy of using EGCG (Epigallocatechin gallate) modified black phosphorus quantum dots (BPQDs) as therapeutic nanoplatforms for MIDBW to achieve the synergistic functions of NIR (near-infrared)-response, ROS-generation, sterilization, and promoting wound healing. The electron spin resonance results revealed that EGCG-BPQDs@H had a more vital photocatalytic ability to produce singlet oxygen than BPQDs@H. The inhibition results indicated an effective bactericidal rate of 88.6% against MRSA. Molecular biology analysis demonstrated that EGCG-BPQDs significantly upregulated CD31 nearly fourfold and basic fibroblast growth factor (bFGF) nearly twofold, which were beneficial for promoting the proliferation of vascular endothelial cells and skin epidermal cells. Under NIR irradiation, EGCG-BPQDs hydrogel (EGCG-BPQDs@H) treated MIDBW area could rapidly raise temperature up to 55 °C for sterilization. The MIBDW closure rate of rats after 21 days of treatment was 92.4%, much better than that of 61.1% of the control group. The engineered EGCG-BPQDs@H were found to promote MIDBW healing by triggering the PI3K/AKT and ERK1/2 signaling pathways, which could enhance cell proliferation and differentiation. In addition, intravenous circulation experiment showed good biocompatibility of EGCG-BPQDs@H. No significant damage to major organs was observed in rats.Conclusion sThe obtained results demonstrated that EGCG-BPQDs@H achieved the synergistic functions of photocatalytic property, photothermal effects and promoted wound healing, and are promising multifunctional nanoplatforms for MIDBW healing in diabetics.Graphical Abstract
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FISH & SHELLFISH IMMUNOLOGY
·
2023
·
IF 4.7
Hao Cai,Ke Li,Yilin Yin,Xiaotong Ni,Shiwen Xu
Bis(2-ethylhexyl) phthalate (DEHP) is not only a widely used plasticizer but also a common endocrine disruptor that frequently lingers in water, posing a threat to the health of aquatic organisms . Quercetin (Que) is a common flavonol found in the plant kingdom known for its antioxidant, anti-inflammatory, and immunomodulatory effects. However, it is still unclear whether DEHP can cause pyroptosis and affect the expression of cytokines of grass carp L8824 cells and whether Que has antagonistic effect in this process. In our study, grass carp L8824 cells were treated into four groups after 24 h, namely NC group, DEHP group (1000 μM DEHP), Que group (5 μM Que), and DEHP + Que group (1000 μM DEHP + 5 μM Que). Our results indicate a significant increase in the level of ROS in L8824 cells after exposure to DEHP. DEHP upregulated oxidative stress markers (H 2 O 2 and MDA) and downregulated antioxidant markers (CAT, GSH, SOD , and T-AOC). DEHP also upregulated MAPK and NF-κB signal pathway-related proteins and mRNA expressions (p-p38, p-JNK, p-EPK, and p65). As for cell pyroptosis and its related pathways, DEHP upregulated pyroptosis-related protein and mRNA expressions (GSDMD, IL-1β, NLRP3, Caspase-1, LDH , pro-IL-18, IL-18, and ASC). Finally, DEHP can up-regulated cytokines (IL-6 and TNF-α) expression, down-regulated cytokines (IL-2 and IFN-γ) expression, and antimicrobial peptides (β-defensin, LEAP2, and HEPC). The co-treatment of L8824 cells with DEHP and Que inhibited the activation of the ROS/MAPK/NF-κB axis, alleviated pyroptosis, and restored expression of immune-related indicators. Finally, NAC was applied to reverse intervention of oxidative stress. In summary, Que inhibited DEHP-induced pyroptosis and the influence on cytokine and antimicrobial peptide expression in L8824 cells by regulating the ROS/MAPK/NF-κB pathway. Our results demonstrate the threat to fish health from DEHP exposure and confirmed the harm of DEHP to the aquatic ecological environment and the detoxification effect of Que to DEHP, which provides a theoretical basis for environmental toxicology.
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INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2023
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IF 5.8
Yimin Wang,Yanan Zhang,Zhihui Yang,Lei Zhang,Xiangping Chen,Guliang Yang,Jianfeng Zhan,Shiming Li,Feng He,Guanwei Fan
Psoriasis is an inflammatory skin disease accompanied with chronic papulosquamous lesions and multiple comorbidities that considerably affect patients’ quality of life. In order to develop an enhanced therapeutic strategy for psoriasis, 5-demethylnobiletin (5-DN), a kind of polymethoxyflavones (PMFs) with high anti-inflammatory activity, was delivered in vitro and in vivo by the nanocarrier of mesoporous silica nanoparticles (MSNs) both in the human keratinocytes HaCaT cell line and the mouse model with psoriasis-like lesions. The drug-loaded nanocarrier system (MSNs@5-DN) significantly improved the biocompatibility and bioavailability of 5-DN. Investigations at cell biological, histopathological, and molecular levels revealed the pharmacological mechanism of the drug delivery system, including the inhibition of inflammatory responses by downregulating the proinflammatory cytokine levels of tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6). The upregulation of anti‑inflammatory cytokine of transforming growth factor-β1 (TGF-β1) and microRNA-17-5p, a critical regulator of the PTEN/AKT pathway, was also observed. The psoriasis-like lesions were markedly ameliorated in the mouse models treated with MSNs@5-DN. The designed drug-loading system shows an enhanced therapeutic outcome for psoriasis-like lesion compared with free 5-DN. This study revealed the synergistic effect of functionalized MSNs loaded with PMFs on the clinical treatment of human psoriasis.
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JOURNAL OF INORGANIC BIOCHEMISTRY
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2021
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IF 4.155
Rui-Xue Liu,Ru-Yi Luo,Meng-Ting Tang,Yan-Cheng Liu,Zhen-Feng Chen,Hong Liang
Based on the anticancer pharmacophore of anthrahydrazone and quinoline, a new quinolylanthrahydrazone ligand, 9-AQH (anthracene-9-quinolylhydrazone), was synthesized to further afford four metal complexes, [Co II (9-AQH)(NO 3 ) 2 (H 2 O)] ( 1 ), [Ni II (9-AQH) 2 (H 2 O) 2 ]·2NO 3 ( 2 ), [Cu I (9-AQH) 2 ]·NO 3 ( 3 ), [Zn II (9-AQH) 2 (NO 3 )]·NO 3 ( 4 ), determined by X-ray single crystal diffraction analysis. The reaction of Cu(NO 3 ) 2 with 9-AQH formed the stable and repeatable copper(I) complex 3 . In vitro screening demonstrated only 3 showed significant and broad-spectrum anticancer activity , indicating that Cu(I) played a key role in exerting the anticancer activity. In solution, Cu(I) was not naturally oxidized to Cu(II) suggested by 1 H-NMR (Nuclear Magnetic Resonance) and EPR (Electron Paramagnetic Resonance) analysis. The presence of 3 could also catalyze the H 2 O 2 system to give hydroxyl free radicals , suggested by further EPR and electrophoresis assay. At the cellular level, although no obvious Cu(II) signals were detected and the total ROS (Reactive Oxygen Species) scavenging in the tumor cells treated with 3 , the potential redox property between Cu(I)/Cu(II), as a key role, should not be denied for the significant anticancer activity of 3 , considering the much complicated circumstance and other reductive substances in cells. The anticancer mechanism of 3 on the most sensitive MGC-803 cells pointed to significant cell apoptosis through mitochondrial pathway, rather than cell cycle arrest . While the autophagy observed in tumor cells treated by 3 suggested its complicated anticancer mechanism, and whether there was an intrinsic correlation still needed to be further investigated.
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PHYTOMEDICINE
·
2021
·
IF 5.34
Shusheng Fan,Xiaoyun Liu,Yu Wang,Xueyang Ren,Yue Liu,Ying Dong,Qiqi Fan,Jing Wei,Jiamu Ma,Axiang Yu,Ruolan Song,Hong Sui,Meng Shen,Fang Fang,Qing Xia,Gaimei She
Background Thymus quinquecostatus Celak. has been widely used as a spice and a folk medicine for relieving exterior syndrome and alleviating pain in China. Purpose To explore the protective effects and the underlying mechanism against cerebral ischemia-reperfusion injury (CIRI) of the T. quinquecostatus combining with its chemical composition. Study design and methods High-polar extract (HPE) was extracted from T. quinquecostatus and polyphenols in HPE were enriched to obtain polyphenol-rich fraction (PRF) using Macroporous resin. The free radicals and zebrafish embryos were used to compare the antioxidant activities of HPE and PRF in vitro and in vivo . Then, the transient middle cerebral artery occlusion (tMCAO) model was established in rats. Neurological deficit score, infarction rate, morphology and apoptosis of neurons were examined to investigate the protective effects of PRF on CIRI. The mRNA and protein levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and hemeoxygenase-1 (HO-1) and the activities of downstream antioxidant enzymes in ischemia tissues were determined to clarify the underlying mechanisms. Also, reactive oxygen species (ROS) level in zebrafish embryos were detected after incubation with PRF for a short time (2 h) to investigate whether PRF could directly eliminate free radicals. Finally, chemical composition of PRF were analyzed to investigate the material basis for antioxidant activity and anti-CIRI effect. Results Compared with HPE, PRF showed stronger antioxidant activities. PRF exhibited obvious protective effects including ameliorating neurological deficit, lowering infarction rate, and improving the cellular morphology in hippocampus CA1 and cortex after tMCAO. TUNEL staining suggested PRF dose-dependently improved the apoptosis of the neurons in ischemic cortex. RT-qPCR and Western Blot results suggested that PRF regulated oxidative stress (OS) via activating the Keap1/Nrf2/HO-1 signaling pathway . Also, PRF could directly scavenge excessive ROS in zebrafish embryos after a short-time PRF incubation. The anti-CIRI effect might be primarily attributed to the abundant polyphenols in PRF, including flavonoids , polymethoxylated flavonoids, flavonoid glycosides , and phenolic acids. Conclusion T. quinquecostatus contains abundant polyphenols and exhibited a good protective effect against CIRI via dual antioxidant mechanisms, providing a reference for further research and application for this plant.
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ACS Applied Materials & Interfaces
·
2020
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IF 8.758
Tianxu Fang,Jun Zhang,Tiantian Zuo,Guangyu Wu,Yingxin Xu,Yifan Yang,Jie Yang,Qi Shen
Extracellular matrix (ECM) accumulating in the tumor microenvironment (TME) is generated by tumor-associated fibroblasts. It can elevate interstitial fluid pressure and form dense barriers in tumor tissues. Consequently, nanocarriers are hindered from permeating into deeper tumor sites. Thus, the programmed drug-releasing nanoparticles, G(TM)PPSP, were developed for TME remodeling and breast cancer therapy. Gelatin nanoparticles were linked with platinum nanoparticles (PtNPs) to obtain G(TM)PPSP with a size of 214.0 ± 5.0 nm. Telmisartan (TM) was loaded in gelatin nanoparticles. Paclitaxel (PTX) was attached to PtNPs via a dual redox responsive diselenide bond. TM release was mediated by MMP-2 because of gelatin degradation in TME, and then intracellular PTX was released because of diselenide linkage fracture triggered by ROS or glutathione. ECM was depleted owing to TGF-β downregulation by TM and direct ablation by the photothermal effect of PtNPs. 4T1 tumor progression was inhibited by PTX chemotherapy, intracellular ROS scavenging of PtNPs, and photothermal therapy (PTT). The tumor spheroid penetration assay proved G(TM)PPSP could permeate into deep tumor regions when MMP-2 existed. In vivo antitumor experiments implied G(TM)PPSP with PTT could inhibit tumor growth effectively and remodel TME via ECM depletion and immunity activation, indicating the potential of G(TM)PPSP-based chemo-photothermal combination therapy for breast cancer treatment.
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Stem Cell Research & Therapy
·
2019
·Vol. 10
·期 1
·1-11
·
IF 4.627
Liao Naishun,Shi Yingjun,Zhang Cuilin,Zheng Youshi,Wang Yingchao,Zhao Bixing,Zeng Yongyi,Liu Xiaolong,Liu Jingfeng
Background Adipose tissue-derived mesenchymal stem cells (ADSCs) are promising candidates for regenerative medicine. However, long-term in vitro passaging leads to stemness loss and cell senescence of ADSCs, resulting in failure of ADSC-based therapy. Methods In this study, ADSCs were treated with low dose of antioxidants (reduced glutathione and melatonin) with anti-aging and stem cell protection properties in the in vitro passaging, and the cell functions including stem cell senescence, cell migration, cell multidirectional differentiation potential, and ROS content were carefully analyzed. Results We found that GSH and melatonin could maintain ADSC cell functions through reducing cell senescence and promoting cell migration, as well as by preserving stemness and multidirectional differentiation potential, through inhibiting ROS generation during long-term expansion of ADSCs. Conclusions Our results suggested that antioxidant treatment could efficiently prevent the dysfunction and preserve cell functions of ADSCs after long-term passaging, providing a practical strategy to facilitate ADSC-based therapy.
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